The goal of this project is to develop a novel drug treatment for schizophrenia that would have minimal liability to produce extrapyramidal side effects, tardive dyskinesia, or sedation. A consensus has emerged from receptor studies and behavioral experiments in animals and humans, that the sigma receptor may mediate some drug-induced (benzomorphan, PCP) psychotomimetic effects as well as be responsible for the actions of haloperidol and some newly proposed antipsychotic drugs. We have exclusive world-wide patent licensing rights to a series of analogs of Di-ortho- tolyl-guanidine (DTG), one of the most selective and potent sigma receptor ligands. In Phase I this project we succeeded in characterizing the most promising DTG analogs for receptor specificity and blood brain barrier permeability. With several of the compounds, we also scaled up the chemical synthesis and produced evidence, in animal tests, of antipsychotic effect with minimal side effect liability. The goals of Phase II of this project are to further characterize the lead compounds biochemically and physiologically in ways that will aid the development process. At the same time we will initiate the development steps necessary to obtain an IND. These will include bulk chemical synthesis, development of a chemical assay, pharmacology safety and metabolism studies and full-scale toxicity testing.